Bone metabolism Flashcards
1
Q
Where is calcium in the body?
A
- 99% sequested in bone
- 1% in extracellular fluid
2
Q
What is calcium important for ?
A
- Bones
- nerve
- muscle
- hormone function
- clotting
3
Q
A
4
Q
what is plasma calcium found as?
A
- 50% bound to albumin
- 50% free
- maintained at level 2.2-2.6mmol/L
5
Q
Where is the calcium absorbed from?
A
- The dudodenum
- by active transport
- mediated by calcium- binding protein and ATP
- regulated by 1,25 dihydroxycholcalciferol (1,25 (OH)2- vitamin D3 via passive diffusion by the jejunum
6
Q
What precentage of calcium filtered by kidneys is reabsorbed?
where does this occur?
A
- 99%
- 60% in proximal convoluted tubules
7
Q
Where is phosphate found?
A
- 85% stored in bone
- functions as metabolite and buffer in enzyme systems
- circulates unbound in plasma
- daily requirement is 1-1.5g/day
- dietary intake is usually sufficient
8
Q
What is the recommended intake of calcium for children/ 10-25 yrs, 25-65yrs, lacation, post menopause females?
A
- CHildren 600 mg/day
- 10-25 yrs 1400 mg/day
- 25-65 yrs 750 mg/day
- lactation 2000 mg/day
- post menopausal female 1500 mg/day
9
Q
How is vitamin D obtained?
what is its role?
A
- Naturally occuring steriods are ingested from fish oils and plants
- activated by skin by UV light
- they enhance calcium and phosphorous absorption across the small intestine via promotion and synthesis of calcium transporting protein and enhance osteoclastic resorption from bone , increasing serum **levels of calcium and phosphate **
- vitamin D also inhibits PTH
10
Q
How does the activation process of vitamin D occur?
A
- UV light-> transforms 7 dehydrocholestrol to cholecalciferol ( vitamin D3)
- hydroxylated in liver -> 25 hydroxycholecalciferol ( 25(OH) vitamin D3)
- serum 25 hydroxycholecalciferol is the most accurate indicator of body vitamin D stores
- further hydroxylation of 25 hydroxycholecalciferol occurs in mitochondria of proximal convulted tubular cells of kidney-> 1.25 dihydroxycholcalciferol ( 1.25(OH)2- vitamin D3- active form of vitamin D
11
Q
What activated vitamin D metabolism?
A
- Low serum calcium/ phosphate
- High PTH
12
Q
What happens to vitamin D when there is low levels of PTH or increased levels of CA/Po4?
A
- Convserion of active 1,25 dihydroxycholecalciferol to inactive 24,25( OH)2 vitamin D3
13
Q
What is parathyroid hormone?
A
- 84 amino acid peptide
- secreted by chief cells of the 4 parathyroid glands in the response to changes in EC calcium via calcium sensing receptor
14
Q
When in PTH secreted?
A
- In response to decreased serum calcium/phosphate
15
Q
When is PTH inhibited by?
A
- elevated serum calcium
- elevated 1,25 dihydroxylcalciferiol
16
Q
What is PTH actions in the kidney?
A
- Stimulate of hydroxylation of 25 hydroxycalciferol 25(OH)- vitamin D3, in the proximal tubules-> indirect intestinal effects
- increased reabsoption of filtered calcium in the kidney
- promotion of urinary excretion of phosphate from kndney
17
Q
What is PTH actions in the bone?
A
- stimulates osteoclasts
- stimulates precursors
- -> bone reabsorption
18
Q
What is PTH overall effect?
A
- Serum calcium levels are increased and phosphate levels are decreased
19
Q
What is calcitonin?
A
- 32 aminoacid peptide
- secreted by the parafollicular C cells of Thyroid gland
20
Q
When is Calcitonin secreted?
A
- In reponse to elevated serum calcium
21
Q
When is calcitonin inhibited?
A
- by decreased serum calcium
22
Q
What does calcitonin do?
A
- Directly inhibits osteoclasts ( have calcitonin receptors
23
Q
What are calcitonin effects?
A
- Include reduction of cellular motility
- retraction of cytoplasmic extensions
- reduction of ruffled osteoclast border
- this produces a transient decrease in serum calcium
24
Q
What is the effect of oestrogen?
A
- Inhibits bone reasorption and therefore prevents bone loss
- also inhibits bone formation
- does not increase bone density
25
Q
What is the effect of corticosteriods on bone?
A
- Reduce GI absorption
- increase renal excretion of calcium thus inhibiting bone matrix formation-> hyperparathyroidism-> rapid bone loss
- pts on corticosteriods should be given calcium and vitamin D with or without bisphosphonates
26
Q
What do thyroid hormones have on the bone?
A
- Increase bone turnover
- favouring bone absorption ( seen in hyperthyroidism)
27
Q
What do growth hormones do to bone?
A
- Produce a positive calcium balance by increasing gut absorption
28
Q
What does insulin do to bone loss?
A
- Type i if poorly controlled may lead to bone loss
29
Q
What do growth factors IL1, IL6 TNF alpha, IGF & TGF do to bone loss?
A
- IL1, IL-6 , TNF alpha stimulate proliferation of osteoclast precursors
- IGF activates osteoblasts, produced by osteoblasts
- TGF activates osteoblasts, also stimulates osteoclastic precursors in vitro
30
Q
What happens to bone mass with age?
A
- Increases up to a peak between 16-25yrs
- after this there is a normal phsyiological loss of bone mass over time for both men and women of 0.3-0.5 % per year
- thus calcium balance is positive in the first decades of life after which it becomes negative
- women have an increase in bone loss up to 2-3% at the menopause but after the first menopausal decade the rate of bone loss is equivalent for both men and women
31
Q
What is bone’s 3 main function?
A
- primary reservoir of calcium
-
Haemopoietic marrow
- located in cancellous bone supplies the body’s cells. tissues and organs with erythrocyte, leukocytes and platelets
- Bone has a mechanical role in supporting the body’s tissues
32
Q
What is woven bone?
A
- collagen fibres are aligned randomly
- no lamellae-> bone weaker
- more flexible
- isotrophic characteristics- uniform properties in all directions
33
Q
Where is woven bone found?
A
- Embryonic/ Neonatal skeleton
- metaphyseal region of growing bones
- fx callus of children
- absent in normal adult but appears in hard callus following fx
- also found in pathological fx- Pagets/osteogenesis imperfecta
34
Q
What forms cortical and cancellous bone?
A
- Lamellar ( mature) bone
- with stress orientated fibres
- leads to an aniostrophic characteristic
35
Q
What cells lay down lamella bone?
A
- Osteoblasts
36
Q
Within each lamella what do the collagen fibres do?
A
- Run at oblique angles to each other- herring bone
- Cement lines separate the lamella
37
Q
What is lamella bone composed of?
A
- predominantly a matrix with a small population of osteocytes ( trapped osteoblasts) encased within bony lacunae and resting bone lining cells ( with osteoblastic potential) covering the bony surfaces
38
Q
Decribe cortical bone?
A
- 80% of adult skeleton
- lamella laid down in concentric rings-> tubular lamellar systems= osteons/Haversian systems
- approx 50um diameter
- individual osteons are aligned along lines of force (usually parallel with the long axis of the bone)
- each osteon has a central haversian canal surrounded by 5-7 concentric rings of lamella
- cement lines- separate osteons
39
Q
How do the osteocytes within the osteons communicate?
A
- Via gap junctions within channels = canaliculi
40
Q
What is the name of the second set of canals that penetrate the cortical bone?
what is there function?
A
- Volkmann’s canal
- run perpendicular to the long bone axis connecting inner an outer surfaces of bone
- canals carry blood vessels to and from the haversian system
41
Q
What is the young’s modulus of cortical bone?
A
- YM 20GPa cf cancellous 1GPa
- cortical bone is more resistant to bending and torsion
- Denser
42
Q
Where is cancellous bone found?
A
- metaphysis and epiphysis of long bones
- centrally in cuboid bones
43
Q
What is the structure of cancellous bone?
A
- 3d lattice of interconnecting tabeculae which are alignes along axis of mechanical stress, enclosing elements of the bone marrow
- each of the trabeculae is made up of parallel sheets of lamella
- osteocytes, lacunae adn canaculi similar to cortical bone
- No haversian systems
- x8 turnover rate of cortical bone due to large surface area
- less dense, less elastic, brittle& less strong than cortical bone
44
Q
Describe the layers of the periosteum?
A
- Inner cambial layer- loose, vascular , oseogenic
- outer fibrous layer- more structural, less cellular and continuous with joint capsules
- with age the periosteum thins adn has less osteogenic potential
45
Q
What is bone?
A
- Composite materal consisting of cells 10% and matrix 90% that has inorganic and organic compotents
46
Q
Describe the cells of bone?
A
- Osteoblasts
- Osteocytes
- Bone lining cells
- Osteoclasts
47
Q
What are osteoblasts?
A
- from Undifferentiated Mesenchymal stem cells in marrow
- Produce osteoid ( bone forming cells) - contains type 1 collagen, deposied in pre-exisiting mineralised surfaces
- Have great Synthetic capacity ( abundant rough endoplasmic reticulum, golgi apparatus and mitochondria)
- show high alkaline phosphatase activity
- mediated by bone morphogenic proteins,growth factors and cytokines
- 3 fates
- become inactive bone - lining cells
- surround with matrix-> osteocytes
- undergo apoptosis
48
Q
What are osteocytes?
A
- osteoblasts that become entrapped by calcified bone matrix
- 90% of bone cell population
- interconnect via long cytoplasmic processes in the canaliculi
- important in controlling calcium and phosphorous metabolism- respond to PTH/Calcitonin/ mechanical and electrical potential
49
Q
What are bone lining cells?
A
- Flat cells lying on the surface of the bone possess cytoplasmic extensions that pentrate bone matrix & communicate with osteocytes
- **Inactive osteoblasts **that may be reactivated to become osteoblasts
- Gatekeeper function: when stimulated by PTH, they undergo cyclic adenosine monophosphate (cAMP) mediated morphological changes that expose the bone surface and allow osteoclasts to start resorption
50
Q
What are osteoclasts?
A
- Mononuclear osteoclast precursor cells (preosteoclasts) arise from haematopoietic macrophage and monocyte stem-cell line
- found in marrow and circulating blood
- When stimulated these cells proliferate & fuse -> large multinucleated osteoclast
- typically 3-20 nuclei, large no of mitochondria and lyosomes that produce acid phosphatase
- osteoclasts reabsorb bone within pits = Howship’s lacunae on endosteal/periosteal surface of bone
- Ruffles ( brush) border that increases surface area which binds to bone surface via Integrins, sealing the area
- A low pH is produced beneath this area ( via carbonic anhydrase system, adenosine triphosphate dependent proton pumps and the Na/H+ exchange system which dissolves the inorganic apatite crystals
- Acid protelytic lysosomal enzymes, such as tartrate-resistant isoenzyme of acid phosphatase ( TRAP) and cysteine proteinases such as cathepsin then hydrolyse the organic matrix components
- In dense cortical bone, OC lead cutting cones that tunnel thru the bone creating resorption cavities
- control of OC is related to OB
51
Q
What is a bone remodelling unit?
A
- is an area of remodelling by a set of osteoblasts. osteoclasts and stromal supporting tissue
- in normal bone formation matches resorption with continual turnover of bone
- osteoclast precursors are activated -> osteoclasts which reabsorb bone
- this is followed by reversal , whereby osteblast precursors are activated to form osteoblasts which lay down osteoid, which undergoes mineralisation to form bone
52
Q
What does the bone matrix consist of?
A
- Inorganic matrix 60% - resists compression forces
- Organic matrix 40% - resists tensile forces
53
Q
What is the inorganic matric composed of?
A
- Calcium phosphate crystals analogous to calcium hydroxyapatite
- Ca10 ( PO4)6(OH)2
- Mineralisation-= formation of solid calcium phosphate crystals
- Osteocalcium phosphate ( brushite)- also in bone
- serves as reservoir 99% body’s calcium, 85% phosphorous, 40-60% Na/K
54
Q
What is the composition of the organic matrix?
A
- Collagen type 1 =90% of organic matrix
- triple helix of 2x alpha1 and 1x alpha2 chains with a repitive Gly XY sequence where glycine is the first position and X and Y are often proline/hydroxyproline arranged in a quarter staggered structural array-> single fibrils
- responsible for the tensile strength of bone
- small amount of V and XI collagen
-
Bone specific proteoglycans
- invovled in mineralisation/organistion of collagen fibres/binding of growth factors
-
Non collagenous matrix proteins
- Osteocalcin
- Osteonectin
- OSteopontin
- bone sialoprotein II
-
Growth factors/cytokines
- BMP-17 ( members of transforming growth factor beta)
- Insulin growth factor I & II
- Interleukins 1 &** 6**
55
Q
What is Osteocalcin?
A
- produced by osteoblasts
- involved in control of osteoclasts
- gene on chromosome 1
56
Q
What is Osteonectin?
A
- Secreted by Osteoblasts and platelets
- regulation of mineralisation
- gene on chromosome 5
57
Q
What is osteopontin?
A
- A non bone specific cell- binding protein anchoring osteoclasts to mineralised matrix
- gene on chromosome 4
58
Q
What is a good marker of bone turnover?
A
- Hydroxyproline
59
Q
What is a good indiator of bone formation?
A
- Pro-collagen
- collagen telopeptides- carboxy-terminal
- bone specific alkaline phosphatase
- osteocalcin
60
Q
What is a good indicator of bone breakdown?
A
- Pyridinoline and deoxypyridinoline
- X linkages formation beween adjacent triple helices are broken down
61
Q
What is the blood supply to the bone?
A
- Nutrient artery system- (high pressure )
- Metaphyseal- epiphyseal system
- Periosteal system ( low pressure)
62
Q
Describe the nutrient artery system?
A
- Major artery enters the mid-diaphysis thru a nutrient foramen
- once in medullary canal it divides into ascending and descending arteries or arterioles which anastomose with metaphsyeal vessels and directly penetrate the endosteal surface supplying the inner 2/3rd cortex
- in a child these vessels end on the metaphyseal side of the physis, contributing to process of endochondrl ossification
- at microscopic level, arterioles run in volkmann’s canals with branches to the haversian systems, draining to venules and then into central venous sinus and out via the nutrient vein
63
Q
Describe the metaphsyeal-epiphyseal system?
A
- Periarticular system complex penetrates the thin cortex and supplies the metaphysis, physis and epiphysis.
- the metaphyseal vessels anatomose with the medullary and epiphyseal arteries after the growth plate fusion
- in epiphysis with large articular surfaces such as radial and femoral heads, vessels enter the bone between articular cartilage and the physis, making the supply tenuous
64
Q
Describe the periosteal system?
A
- Capillaries enter at the sites of major muscle attachments, normally supplying outer 1/3rd of teh cortex
- this is the domiant system in children- responsible for circumferential growth
*
65
Q
what is the normal direction of blood fow in the bone?
A
- Centrifugal
- ie inside to out
66
Q
What happens to bone blood flow after IM nailing?
A
- The endosteal blood suuply is damaged
- the **periosteal system becomes dominant **
- so the flow -> Centripetal = out to in
- venous blood system is normally centripetal
